Epistatic interactions are critical to gene-association studies: PAI-1 and risk for mortality after burn injury.

Replication of statistically significant associations between single nucleotide polymorphisms (SNPs) and disease phenotypes has been problematic. One reason for conflicting observations may be failure to consider confounding factors, including gene-gene (epistatic) interactions. Our experience with the insertion/deletion polymorphism at -688 in the promoter region of plasminogen activator inhibitor (PAI-1) seems to support this contention and may foreshadow problems for genome-wide association scans, which tend to use unadjusted analytical methodologies. One hundred forty-nine patients with > or =15% total body surface area (TBSA) burns, without significant nonburn-related trauma (injury severity score < or =16), traumatic or anoxic brain injury or spinal cord injury who survived >48 hours postadmission were enrolled under a protocol approved by the UT Southwestern and Parkland Hospital IRBs. Clinical data were collected prospectively and candidate polymorphisms in PAI-1 (-688), toll-like receptor 4 (+896), CD14 (-159), tumor necrosis factor-alpha (-308), and interleukin-6 (-174) were genotyped. The PAI-1 SNP was significantly associated (P-value for trend = 0.036) with risk for death when evaluated in isolation by unadjusted analysis. However, after adjustment for potential confounders using multiple logistic regression, only age, full-thickness burn size, and CD14 genotype (as previously reported) were associated with increased mortality. Genetic association analyses should be adjusted for interactions between multiple SNPs, injury or disease characteristics, and demographic variables. Increasingly sophisticated analytical methods will be required as gene-mapping studies transition from a candidate-gene based approach to genome-wide association scans.     

Sarcoidosis of the skin – A dermatological puzzle: important differential diagnostic aspects and guidelines for clinical and histopathological recognition

Sarcoidosis of the skin may have an extremely heterogeneous clinical presentation, so that the definitions of ‘great imitator’ and ‘clinical chameleon’ have long been used. There is, in fact, a large group of skin diseases that can enter the differential diagnosis with cutaneous sarcoid manifestations, either clinically or/and pathologically. As the clinical consequences and the prognosis of these groups of diseases are often very different, it is important to correctly plan the diagnostic workup. The diagnostic process in this case often presents a challenge as no single test is sufficiently specific, so that a certain diagnosis can be only made in the presence of a compatible clinical and radiographic picture, along with histopathological evidence of non‐necrotizing, epithelioid cell granulomas, and exclusion of other potential aetiologies. For practical reasons, four main groups of skin conditions capable of mimicking sarcoidosis can be identified: (i) transmissible, infectious diseases; (ii) allergic and immunological manifestations of various aetiologies; (iii) granulomatous diseases of various aetiologies; and (iv) lymphomas and pseudolymphomas. The aim of this article is to describe the main clinical and histopathological findings of such disease entities, and to discuss the role of those features (morphological, pathological and laboratory) that can help distinguish them from sarcoidosis of the skin.     

Vitamin D deficiency does not alter biochemical markers of bone metabolism before or after autograft in patients with multiple myeloma

So far, only one study has demonstrated a high incidence of vitamin D deficiency in patients with multiple myeloma. Vitamin D deficiency may alter bone remodelling in myeloma. In this study, we aimed to determine the prevalence of vitamin D deficiency and to assess its impact on bone remodelling and bone mineral density before and after autologous stem cell transplantation (ASCT). Patients and methods: In 39 consecutive patients receiving high‐dose chemotherapy (melphalan 200 mg/m²) followed by ASCT for multiple myeloma, we measured before (T0) and 12 months after ASCT (T12) serum calcium, 25‐OH‐D, PTH 1‐84, bone alkaline phosphatase (bALP), serum C‐terminal cross‐linking telopeptide and lumbar spine bone mineral density (BMD). Results: Mean vitamin D levels were low: 15 ± 5 ng/mL (9–18) at T0 and 16 ± 5 ng/mL (14–22) at T12. Twenty‐six patients (68%) had vitamin D deficiency (25‐OH‐D < 20 ng/mL) at T0 and 58% at T12. Patients in the vitamin D‐deficient group had higher serum PTH levels than those in the vitamin D‐sufficient group : 71 ± 24 pg/mL vs. 52 ± 18 pg/mL (P = 0.04). Biochemical bone markers were identical in both groups at T0 and T12. Z‐score values did not significantly differ between the two groups at T0 and T12. There were no correlations between 25‐OH‐D and BMD or bone marker levels. Conclusion: Vitamin D deficiency does not impair biochemical markers of bone metabolism in patients with multiple myeloma, before or after ASCT.     

Posttraumatic psoriatic osteitis of the frontal bone successfully treated with etanercept. Report of a case

We report a case of aseptic osteomyelitis of the frontal bone that developed after a local injury in an 8-year-old girl with psoriasis of the scalp as a predisposing factor. Follow-up was 36 years (1972 to 2008). Enthesitis of the forehead muscles was a plausible pathophysiological mechanism. The symptoms responded to anti-inflammatory medications and resolved immediately after the introduction of etanercept therapy. The most interesting feature of this case of psoriatic osteomyelitis is the involvement of a skull bone.     

Nummular headache: a series with symptomatic and primary cases

Nummular headache (NH) is a primary headache adopting the form of local pain in a circumscribed area of < 7 cm in diameter in the tuber parietale, albeit it may also be located in other areas of the head. Although it is chronic, it is commonly associated with exacerbations and short periods of remission. Here we report four cases. Two of them could not be considered primary: in one the pain was related to an underlying, pointed and benign lesion disclosed only by magnetic resonance imaging (case 1); the second one had persistent NH days after trans-sphenoidal surgery for a pituitary adenoma, similar to a postcraniotomy headache (case 2). The two final patients suffered from typical forms of primary NH, one associated with migraine without aura, the other with chronic tension-type headache. The response to pain-related treatments and to preventive drugs was poor in the symptomatic as well as in the primary cases. The mechanisms are not clear, and peripheral (case 1) and also central pathways (case 2) could be involved. In the end, secondary forms of NH might coexist with classical primary NH. Particular attention should be paid to tiny skull lesions and to key events preceding the pain.     

Intraoperative acceleration measurements to quantify improvement in tremor during deep brain stimulation surgery

Deep brain stimulation (DBS) surgery is extensively used in the treatment of movement disorders. Nevertheless, methods to evaluate the clinical response during intraoperative stimulation tests to identify the optimal position for the implantation of the chronic DBS lead remain subjective. In this paper, we describe a new, versatile method for quantitative intraoperative evaluation of improvement in tremor with an acceleration sensor that is mounted on the patient’s wrist during surgery. At each anatomical test position, the improvement in tremor compared to the initial tremor is estimated on the basis of extracted outcome measures. This method was tested on 15 tremor patients undergoing DBS surgery in two centers. Data from 359 stimulation tests were acquired. Our results suggest that accelerometric evaluation detects tremor changes more sensitively than subjective visual ratings. The effective stimulation current amplitudes identified from the quantitative data (1.1 ± 0.8 mA) are lower than those identified by visual evaluation (1.7 ± 0.8 mA) for similar improvement in tremor. Additionally, if these data had been used to choose the chronic implant position of the DBS lead, 15 of the 26 choices would have been different. These results show that our method of accelerometric evaluation can potentially improve DBS targeting.     

Early severe weight loss in newborns after discharge from regular nurseries

Aims: To study incidence and risk factors of early neonatal dehydration in a Norwegian population based cohort. Methods: Term neonates admitted to a paediatric department during 2002–2008 with a weight loss ≥ 12% within three weeks of age were identified retrospectively through review of medical records. For each patient a sex‐matched control group of two full‐term infants was selected to assess risk factors for dehydration. Results: A total of 38 of 37 321 infants (1.0‰) were admitted at a median age of 6 (interquartile range 5–12) days, and the admission rate increased during the study period (p for trend = 0.008). Simultaneously, mean nursery stay decreased from 3.5 to 2.7 days (p = 0.022). Mean weight loss was 15.0% of birth weight and 17 of 29 (58.6%) had serum sodium above 145 mmol/L. The only significant difference between patients and controls was that mothers of patients were older (32.3 ± 5.0 vs. 29.4 ± 5.4 years, p = 0.005). Conclusion: Short nursery stay may be a risk factor for dehydration in newborn infants.     

Role of positively charged transmembrane segments in the insertion and assembly of mitochondrial inner-membrane proteins

The biogenesis of membrane oligomeric complexes is an intricate process that requires the insertion and assembly of transmembrane (TM) domains into the lipid bilayer. The Oxa1p family plays a key role in this process in organelles and bacteria. Hell et al. (2001, EMBO J., 20, 1281-1288) recently have proposed that Oxa1p could act as part of a general membrane insertion machinery for mitochondrial respiratory complex subunits. We have previously shown that mutations in the TM domain of Cyt1p can partially compensate for the absence of Oxa1p. Here, we demonstrate that a single amino acid substitution in the TM domain of Qcr9p can bypass Oxa1p in yeast. Qcr9p and Cyt1p are two subunits of the respiratory complex bc1 and their relative roles in the assembly of other respiratory complexes have been investigated. The mutations we have isolated in Cyt1p or Qcr9p introduce positively charged amino acids, and we show that the mutant TM domain of Cyt1p mediates the restoration of complex assembly. We propose that the positive charges introduced in Cyt1p and Qcr9p TM domains promote interactions with negatively charged TM domains of other respiratory complex subunits, allowing the coinsertion of both domains into the membrane, in the absence of Oxa1p. This model argues in favor of a role of Oxa1p in the insertion and the lateral exit of less hydrophobic TM domains from the translocation site into the lipid bilayer.